Maintenance of organelle identity in the endo-lysosome system is profoundly dependent on the coordination between correct targeting of proteins and removal of mistargeted and damaged proteins. This task is mediated by organelle-specific protein quality control (QC) systems. The endo-lysosome PQC pathway monitors membrane proteins at the cell surface, and along the endocytic pathway at the trans-Golgi network (TGN), the endosome, and the lysosome. Our lab is interested in understanding what all players play a key role in protein quality control in the endocytic pathway, how their function and localization is regulated, and which cargos are targeted by them for degradation in response to specific cues.
Our work has demonstrated that Rsp5, the yeast homolog of human Nedd4 HECT E3 Ub-ligases, plays a critical role in ubiquitin-dependent trafficking throughout the endocytic system. Rsp5 is recruited to target proteins in distinct organelles by specific ‘adaptors’ that facilitate its broad substrate range and accessibility. The ART-Rsp5 network monitors Ub-dependent endocytic cargos at the cell surface (PMQC). Cargos that escape ubiquitination or MVB sorting are exposed to Endosomal QC or are delivered to the vacuole membrane upon fusion of the endosome with the vacuole (yeast lysosome). Ssh4-Rsp5 E3 ligase complex provides the final clearance mechanism to ensure removal of aberrant membrane proteins (Lysosomal QC). The sequential organization of distinct adaptor-Rsp5 Ub-ligase complexes ensures smooth endocytic function and prevents unnecessary accumulation of membrane proteins on the lysosome membrane, the terminal destination of the endocytic pathway.
Key Publications
1. Sardana R, Emr SD. (2021). Membrane Protein Quality Control Mechanisms in the Endo-Lysosome System. Trends in Cell Biology. DOI: 10.1016/j.tcb.2020.11.011.
2. Sardana R, Zhu L, Emr SD. (2019). Rsp5 ubiquitin ligase-mediated quality control system clears membrane proteins mistargeted to the vacuole membrane. J Cell Biol. 218(1):234-250.
3. Li M, Rong Y, Chuang Y, Peng D, Emr SD. (2015). Ubiquitin-dependent lysosomal membrane protein sorting and degradation. Mol Cell 57(3): 467-478.
4. Zhao Y, Macgurn JA, Liu M, Emr SD. (2013). The ART-Rsp5 ubiquitin ligase network comprises a plasma membrane quality control system that protects yeast cells from proteotoxic stress. Elife. 2:e00459.
